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1.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1238060

ABSTRACT

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2-infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.


Subject(s)
Antigen Presentation , COVID-19/immunology , Down-Regulation/immunology , Histocompatibility Antigens Class I/immunology , Immune Evasion , SARS-CoV-2/immunology , Viral Proteins/immunology , Animals , Autophagy/genetics , Autophagy/immunology , COVID-19/genetics , Chlorocebus aethiops , HEK293 Cells , Histocompatibility Antigens Class I/genetics , Humans , Lysosomes/genetics , Lysosomes/immunology , Lysosomes/virology , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells , Viral Proteins/genetics
2.
Cells ; 10(5)2021 05 07.
Article in English | MEDLINE | ID: covidwho-1223961

ABSTRACT

The flavonoid naringenin (Nar), present in citrus fruits and tomatoes, has been identified as a blocker of an emerging class of human intracellular channels, namely the two-pore channel (TPC) family, whose role has been established in several diseases. Indeed, Nar was shown to be effective against neoangiogenesis, a process essential for solid tumor progression, by specifically impairing TPC activity. The goal of the present review is to illustrate the rationale that links TPC channels to the mechanism of coronavirus infection, and how their inhibition by Nar could be an efficient pharmacological strategy to fight the current pandemic plague COVID-19.


Subject(s)
COVID-19/drug therapy , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Flavanones/pharmacology , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Arabidopsis/metabolism , COVID-19/epidemiology , COVID-19/pathology , COVID-19/virology , Calcium Channel Blockers/therapeutic use , Drug Evaluation, Preclinical , Endosomes/drug effects , Endosomes/metabolism , Endosomes/virology , Flavanones/therapeutic use , Humans , Lysosomes/drug effects , Lysosomes/metabolism , Lysosomes/virology , Neoplasms/blood supply , Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Pandemics/prevention & control , SARS-CoV-2/pathogenicity , Vacuoles/metabolism , Virus Internalization/drug effects
3.
Int J Mol Sci ; 22(4)2021 Feb 11.
Article in English | MEDLINE | ID: covidwho-1079663

ABSTRACT

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery , Lysosomes/drug effects , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Chlorpromazine/pharmacokinetics , Chlorpromazine/pharmacology , Chlorpromazine/therapeutic use , Cytokine Release Syndrome/drug therapy , Drug Discovery/methods , Drug Repositioning/methods , Fluvoxamine/pharmacokinetics , Fluvoxamine/pharmacology , Fluvoxamine/therapeutic use , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Interleukin-1/antagonists & inhibitors , Interleukin-1/immunology , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Lung/drug effects , Lung/immunology , Lung/metabolism , Lung/virology , Lysosomes/immunology , Lysosomes/metabolism , Lysosomes/virology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/therapeutic use , Virus Replication/drug effects
4.
Cell Calcium ; 94: 102360, 2021 03.
Article in English | MEDLINE | ID: covidwho-1064903

ABSTRACT

Ion channels are necessary for correct lysosomal function including degradation of cargoes originating from endocytosis. Almost all enveloped viruses, including coronaviruses (CoVs), enter host cells via endocytosis, and do not escape endosomal compartments into the cytoplasm (via fusion with the endolysosomal membrane) unless the virus-encoded envelope proteins are cleaved by lysosomal proteases. With the ongoing outbreak of severe acute respiratory syndrome (SARS)-CoV-2, endolysosomal two-pore channels represent an exciting and emerging target for antiviral therapies. This review focuses on the latest knowledge of the effects of lysosomal ion channels on the cellular entry and uncoating of enveloped viruses, which may aid in development of novel therapies against emerging infectious diseases such as SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/virology , Ion Channels/physiology , Lysosomes/virology , SARS-CoV-2/physiology , Viral Envelope/physiology , Virus Internalization , Virus Uncoating , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Antiviral Agents/pharmacology , Drug Design , Endocytosis , Endosomes/metabolism , Endosomes/virology , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Hydrazones/pharmacology , Hydrazones/therapeutic use , Ion Channels/classification , Lysosomes/enzymology , Lysosomes/metabolism , Models, Biological , Morpholines/pharmacology , Morpholines/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Vacuolar Proton-Translocating ATPases/physiology , Virus Internalization/drug effects , Virus Uncoating/drug effects
5.
Virology ; 556: 9-22, 2021 04.
Article in English | MEDLINE | ID: covidwho-985483

ABSTRACT

Coronaviruses rearrange endoplasmic reticulum (ER) membranes to form a reticulovesicular network (RVN) comprised predominantly of double membrane vesicles (DMVs) involved in viral replication. While portions of the RVN have been analyzed by electron tomography (ET), the full extent of the RVN is not known, nor how RVN formation affects ER morphology. Additionally the precise mechanism of DMV formation has not been observed. In this work, we examined large volumes of coronavirus-infected cells at multiple timepoints during infection using serial-section ET. We provide a comprehensive 3D analysis of the ER and RVN which gives insight into the formation mechanism of DMVs as well as the first evidence for their lysosomal degradation. We also show that the RVN breaks down late in infection, concurrent with the ER becoming the main budding compartment for new virions. This work provides a broad view of the multifaceted involvement of ER membranes in coronavirus infection.


Subject(s)
Coronavirus Infections/virology , Endoplasmic Reticulum/metabolism , Murine hepatitis virus/physiology , Viral Replication Compartments/metabolism , Animals , Cell Line , Electron Microscope Tomography , Endoplasmic Reticulum/ultrastructure , Endoplasmic Reticulum/virology , Lysosomes/metabolism , Lysosomes/ultrastructure , Lysosomes/virology , Mice , Viral Proteins/metabolism , Viral Replication Compartments/ultrastructure , Virion/metabolism , Virus Assembly , Virus Replication
6.
FEBS J ; 287(17): 3664-3671, 2020 09.
Article in English | MEDLINE | ID: covidwho-960850

ABSTRACT

The quest for the effective treatment against coronavirus disease 2019 pneumonia caused by the severe acute respiratory syndrome (SARS)-coronavirus 2(CoV-2) coronavirus is hampered by the lack of knowledge concerning the basic cell biology of the infection. Given that most viruses use endocytosis to enter the host cell, mechanistic investigation of SARS-CoV-2 infection needs to consider the diversity of endocytic pathways available for SARS-CoV-2 entry in the human lung epithelium. Taking advantage of the well-established methodology of membrane trafficking studies, this research direction allows for the rapid characterisation of the key cell biological mechanism(s) responsible for SARS-CoV-2 infection. Furthermore, 11 clinically approved generic drugs are identified as potential candidates for repurposing as blockers of several potential routes for SARS-CoV-2 endocytosis. More broadly, the paradigm of targeting a fundamental aspect of human cell biology to protect against infection may be advantageous in the context of future pandemic outbreaks.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Endocytosis/drug effects , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Amiloride/pharmacology , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Caveolae/drug effects , Caveolae/virology , Chlorpromazine/pharmacology , Clathrin-Coated Vesicles/drug effects , Clathrin-Coated Vesicles/virology , Endosomes/drug effects , Endosomes/virology , Humans , Itraconazole/pharmacology , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/virology , Lysosomes/drug effects , Lysosomes/virology , Nystatin/pharmacology , Pinocytosis/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vinblastine/pharmacology
7.
Front Immunol ; 11: 1409, 2020.
Article in English | MEDLINE | ID: covidwho-680017

ABSTRACT

As the world is severely affected by COVID-19 pandemic, the use of chloroquine and hydroxychloroquine in prevention or for the treatment of patients is allowed in multiple countries but remained at the center of much controversy in recent days. This review describes the properties of chloroquine and hydroxychloroquine, and highlights not only their anti-viral effects but also their important immune-modulatory properties and their well-known use in autoimmune diseases, including systemic lupus and arthritis. Chloroquine appears to inhibit in vitro SARS virus' replication and to interfere with SARS-CoV2 receptor (ACE2). Chloroquine and hydroxychloroquine impede lysosomal activity and autophagy, leading to a decrease of antigen processing and presentation. They are also known to interfere with endosomal Toll-like receptors signaling and cytosolic sensors of nucleic acids, which result in a decreased cellular activation and thereby a lower type I interferons and inflammatory cytokine secretion. Given the antiviral and anti-inflammatory properties of chloroquine and hydroxychloroquine, there is a rational to use them against SARS-CoV2 infection. However, the anti-interferon properties of these molecules might be detrimental, and impaired host immune responses against the virus. This duality could explain the discrepancy with the recently published studies on CQ/HCQ treatment efficacy in COVID-19 patients. Moreover, although these treatments could be an interesting potential strategy to limit progression toward uncontrolled inflammation, they do not appear per se sufficiently potent to control the whole inflammatory process in COVID-19, and more targeted and/or potent therapies should be required at least in add-on.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Hydroxychloroquine/therapeutic use , Pandemics , Virus Replication/drug effects , Angiotensin-Converting Enzyme 2 , Antigen Presentation , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Humans , Lysosomes/immunology , Lysosomes/virology , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , SARS-CoV-2 , Toll-Like Receptors/immunology , Virus Replication/immunology
8.
J Lipid Res ; 61(7): 972-982, 2020 07.
Article in English | MEDLINE | ID: covidwho-382050

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.


Subject(s)
Anticholesteremic Agents/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Intracellular Signaling Peptides and Proteins/genetics , Niemann-Pick Disease, Type C/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Androstenes/therapeutic use , Angiotensin-Converting Enzyme 2 , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , COVID-19 , Cholesterol/metabolism , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Drug Repositioning/methods , Humans , Hydroxychloroquine/therapeutic use , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/metabolism , Lysosomes/drug effects , Lysosomes/metabolism , Lysosomes/virology , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/metabolism , Niemann-Pick Disease, Type C/pathology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Protein Binding , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
9.
FASEB J ; 34(6): 7253-7264, 2020 06.
Article in English | MEDLINE | ID: covidwho-175986

ABSTRACT

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.


Subject(s)
Antiviral Agents/pharmacokinetics , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Drug Repositioning , Endosomes/virology , Hydroxychloroquine/pharmacology , Lysosomes/virology , Niemann-Pick Disease, Type C/pathology , Pneumonia, Viral/drug therapy , ADAM17 Protein/physiology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Biological Transport , COVID-19 , Cathepsin L/physiology , Endocytosis , Endosomes/drug effects , Endosomes/physiology , Glycopeptides/pharmacology , Glycopeptides/therapeutic use , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/deficiency , Intracellular Signaling Peptides and Proteins/physiology , Lysosomes/drug effects , Lysosomes/metabolism , Membrane Lipids/metabolism , Membrane Microdomains/physiology , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/metabolism , Oxysterols/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , SARS-CoV-2 , Serine Endopeptidases/physiology , Triazoles/pharmacology , Triazoles/therapeutic use , Virus Internalization/drug effects
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